Non-invasive prenatal testing of beta-hemoglobinopathies using next generation sequencing, in-silico sequence size selection, and haplotyping.

AIM: To develop a non-invasive prenatal test for beta-hemoglobinopathies based on analyzing maternal plasma by using next generation sequencing. METHODS: We applied next generation sequencing (NGS) of maternal plasma to the non-invasive prenatal testing (NIPT) of autosomal recessive diseases, sickle cell disease and beta-thalassemia. Using the Illumina MiSeq, we sequenced plasma libraries obtained via a Twist Bioscience probe capture panel covering 4 Kb of chromosome 11, including the beta-globin (HBB) gene and >450 genomic single-nucleotide polymorphisms (SNPs) used to estimate the fetal fraction (FF). The FF is estimated by counting paternally transmitted allelic sequence reads present in the plasma but absent in the mother. We inferred fetal beta-globin genotypes by comparing the observed mutation (Mut) and reference (Ref) read ratios to those expected for the three possible fetal genotypes (Mut/Mut; Mut/Ref; Ref/Ref), based on the FF. RESULTS: We bioinformatically enriched the FF by excluding reads over a specified length via in-silico size selection (ISS), favoring the shorter fetal reads, which increased fetal genotype prediction accuracy. Finally, we determined the parental HBB haplotypes, which allowed us to use the read ratios observed at linked SNPs to help predict the fetal genotype at the mutation site(s). We determined HBB haplotypes via Oxford Nanopore MinION sequencing of a 2.2 kb amplicon and aligned these sequences using Soft Genetics' NextGENe LR software. CONCLUSION: The combined use of ISS and HBB haplotypes enabled us to correctly predict fetal genotypes in cases where the prediction based on variant read ratios alone was incorrect.

Sex differences in the association of pretransfusion haemoglobin and cognition in preterm infants.

OBJECTIVES: To assess sex-specific differences in the association between pre-transfusion haemoglobin values and early neurodevelopmental function. DESIGN: Observational follow-up of infants with birth weights <1000 g and gestational ages 22-28 weeks who were enrolled in the NICHD Neonatal Research Network Transfusion of Prematures (TOP) Trial at 19 U.S. sites, 2012-2017. MAIN OUTCOME MEASURES: Pretransfusion haemoglobin values were obtained longitudinally through 36 weeks' postmenstrual age. The infant's mean pretransfusion haemoglobin was used as a marker of degree of anaemia (n=1655 measures). Measures of brain function were obtained at 22-26 months' corrected age using the Bayley Scales of Infant & Toddler Development, third edition (BSID-III) (n=1290 BSID-III scores). Sex-specific estimates for the linear relation between pretransfusion haemoglobin and BSID-III scores were obtained from repeated-measures regression analysis, adjusted for gestational age, birth weight, study site, clinical characteristics, and demographic covariates. RESULTS: The relation of pretransfusion haemoglobin with 24-month BSID-III scores showed significant, independent interactions with both (1) sex (p=0.046) and (2) retinopathy of prematurity (ROP; p=0.004). In 614 males, BSID-III scores were higher by 1.07 points per g/dL (95% CI 1.58 to 4.33; p=0.008), not differing significantly among the three subscales (cognitive, language and motor; p=0.94). In 247 infants with ROP, BSID-III scores were higher by 2.95 points per g/dL (95% CI 0.28 to 1.87; p<0.0001), uniformly across subscales (p=0.73). These associations were non-significant in 676 females (p=0.96) and 1043 infants without ROP (p=0.81). CONCLUSIONS: This study demonstrates sex-specific associations between mean pretransfusion haemoglobin (a marker of the severity of anaemia throughout the neonatal intensive care unit [NICU] hospitalisation) and early neurodevelopmental function at 22-26 months' corrected age.

Respiratory Severity Score and Oxygen Saturation Index during the First 2 Hours of Life as Predictors for Noninvasive Respiratory Support Failure in Respiratory Distress Syndrome.

OBJECTIVE: Noninvasive respiratory support (NRS) failure is common in preterm infants with respiratory distress syndrome (RDS). We evaluated the utility of respiratory severity score (RSS) and oxygen saturation index (OSI) during the first 2 hours of life (HOL) as predictors for NRS failure in moderate preterm infants. STUDY DESIGN: We conducted a retrospective cohort study of infants born between 280/7 and 336/7 weeks with RDS. Univariate and multivariable logistic regression analyses were used to assess whether the RSS and OSI summary measures were associated with NRS failure. RESULTS: A total of 282 infants were included in the study. Median gestational age and birth weights were 32 weeks and 1.7 kg, respectively. Fifty-eight infants (21%) developed NRS failure at the median age of 10.5 hours. RSS and OSI summary measures in the first 2 HOL were associated with NRS failure within 72 HOL. CONCLUSION: RSS and OSI during the first 2 HOL can predict NRS failure. Optimal RSS and OSI cutoffs for the prediction of NRS failure need to be determined in large cohort studies. KEY POINTS: · Nearly one in five moderate preterm infants on NRS at 2 hours of life developed NRS failure.. · RSS and OSI during the first 2 HOL can predict NRS failure.. · Optimal RSS and OSI cutoffs for the prediction of NRS failure need to be determined..

Blood Pressure Pattern and Prevalence of Hypertension amongst Apparently Healthy Primary School Pupils in Abuja, Nigeria.

OBJECTIVES: The objective of this study was to determine the blood pressure (BP) pattern and prevalence of hypertension amongst apparently healthy primary school pupils in Abuja. METHODOLOGY: This was a descriptive, cross-sectional study carried out on apparently healthy primary school children aged 6-12 years. BP was measured using a standard mercury sphygmomanometer according to standard guidelines. Data were analysed using SPSS version 17.0. Pearson's correlation coefficient (r) and analysis of variance were used to determine the relationship between BP and various variables where applicable. P = 0.05 was considered statistically significant. RESULTS: Out of 1011 pupils recruited for the study, 457 (42.2%) were male. The mean systolic and diastolic BP (SBP and DBP) increased significantly with age from 94.5 mmHg to 101.0 mmHg and from 61.5 mmHg to 65.3 mmHg from 6 to 12 years for SBP and DBP, respectively (P < 0.05). The prevalence of high BP was 9.1%. Age was the only predictor of SBP (ß = -0.629, 95% confidence interval [CI] -1.115, -0.142), while age, height and body mass index (BMI) were the predictors of DBP (ß = -0.686, 95% CI of -1.152, -0.221; ß = 0.490, 95% CI of 0.172, 0.809; ß = 1.753, 95% CI of 0.374, 3.160) for age, height and BMI, respectively, at P < 0.05. CONCLUSION: The predictors of SBP and DBP as shown in this study support the recommendations by various reports for taking body size into consideration in developing reference values for various populations. Age and body size are important determinants of BP in children. Its measurement should be encouraged in schools.

Evaluation of Ilex guayusa and Piper marginatum Extract Cytotoxicity on Human Dental Pulp Mesenchymal Stem Cells.

BACKGROUND: Amelogenesis imperfecta is a hereditary disorder affecting dental enamel. Among its phenotypes, hypocalcified AI is characterized by mineral deficiency, leading to tissue wear and, consequently, dental sensitivity. Excessive fluoride intake (through drinking water, fluoride supplements, toothpaste, or by ingesting products such as pesticides or insecticides) can lead to a condition known as dental fluorosis, which manifests as stains and teeth discoloration affecting their structure. Our recent studies have shown that extracts from Colombian native plants, Ilex guayusa and Piper marginatum, deposit mineral ions such as phosphate and orthophosphate into the dental enamel structure; however, it is unknown whether these extracts produce toxic effects on the dental pulp. OBJECTIVE: To assess cytotoxicity effects on human dental pulp stem cells (hDPSCs) exposed to extracts isolated from I. guayusa and P. marginatum and, hence, their safety for clinical use. METHODS: Raman spectroscopy, fluorescence microscopy, and flow cytometry techniques were employed. For Raman spectroscopy, hDPSCs were seeded onto nanobiochips designed to provide surface-enhanced Raman spectroscopy (SERS effect), which enhances their Raman signal by several orders of magnitude. After eight days in culture, I. guayusa and P. marginatum extracts at different concentrations (10, 50, and 100 ppm) were added. Raman measurements were performed at 0, 12, and 24 h following extract application. Fluorescence microscopy was conducted using an OLIMPUS fv1000 microscope, a live-dead assay was performed using a kit employing a BD FACS Canto TM II flow cytometer, and data analysis was determined using a FlowJo program. RESULTS: The Raman spectroscopy results showed spectra consistent with viable cells. These findings were corroborated using fluorescence microscopy and flow cytometry techniques, confirming high cellular viability. CONCLUSIONS: The analyzed extracts exhibited low cytotoxicity, suggesting that they could be safely applied on enamel for remineralization purposes. The use of nanobiochips for SERS effect improved the cell viability assessment.

A study protocol to characterise pathophysiological and molecular markers of rheumatic heart disease and degenerative aortic stenosis using multiparametric cardiovascular imaging and multiomics techniques.

INTRODUCTION: Rheumatic heart disease (RHD), degenerative aortic stenosis (AS), and congenital valve diseases are prevalent in sub-Saharan Africa. Many knowledge gaps remain in understanding disease mechanisms, stratifying phenotypes, and prognostication. Therefore, we aimed to characterise patients through clinical profiling, imaging, histology, and molecular biomarkers to improve our understanding of the pathophysiology, diagnosis, and prognosis of RHD and AS. METHODS: In this cross-sectional, case-controlled study, we plan to recruit RHD and AS patients and compare them to matched controls. Living participants will undergo clinical assessment, echocardiography, CMR and blood sampling for circulatory biomarker analyses. Tissue samples will be obtained from patients undergoing valve replacement, while healthy tissues will be obtained from cadavers. Immunohistology, proteomics, metabolomics, and transcriptome analyses will be used to analyse circulatory- and tissue-specific biomarkers. Univariate and multivariate statistical analyses will be used for hypothesis testing and identification of important biomarkers. In summary, this study aims to delineate the pathophysiology of RHD and degenerative AS using multiparametric CMR imaging. In addition to discover novel biomarkers and explore the pathomechanisms associated with RHD and AS through high-throughput profiling of the tissue and blood proteome and metabolome and provide a proof of concept of the suitability of using cadaveric tissues as controls for cardiovascular disease studies.

Effects of Surgeon-Preferred Staff and Staff Turnover on Operating Time and Complication Rates in Reverse and Anatomic Total Shoulder Arthroplasty.

BACKGROUND: This study focuses on investigating the risk factors of increased operating room time and patient complication rates after total shoulder arthroplasty cases (both reverse and anatomic). We hypothesize that the use of surgeon-preferred staff will improve operating room efficiency and reduce complication rates while increased staff turnover will decrease efficiency and increase complications. METHODS: This is a single-center, retrospective study focused on determining the effects of staffing on operating room time and efficiency in total shoulder arthroplasty. The study included patients who underwent total shoulder arthroplasty by a single fellowship-trained orthopaedic surgeon from 2018 to 2023. RESULTS: Four hundred twenty-three patients were included in the study from August 2018 to April 2023, 264 of which were reverse total shoulder arthroplasty (rTSA) and 159 were anatomic total shoulder arthroplasty (aTSA). In both rTSA and aTSA, the presence of surgeon-preferred staff markedly decreased operating room time. In rTSA, staff turnover increased risk of 90-day complications. CONCLUSION: Because the presence of surgeon-preferred staff affects operating room time and efficiency, orthopaedic surgeons should train multiple surgical teams so that efficiency is not affected by the loss of personnel during a case. To reduce 90-day complication rates in rTSA, staff breaks and turnover should be minimized as much as possible because this has a direct effect on patient outcomes. Effort from hospital administration and management should be put toward reducing turnover to improve patient outcomes.

Polychlorinated biphenyls and incident coronary heart disease-related outcomes in Great Lakes fish consumers.

BACKGROUND: Exposure to polychlorinated biphenyls (PCBs) has been linked to risk factors for cardiovascular disease such as increased inflammation, accelerated atherosclerosis, diabetes, and sex hormone dysregulation. Furthermore, there is increasing evidence suggesting associations between internal dose of PCBs and cardiovascular outcomes. OBJECTIVES: The purpose of this study is to investigate longitudinal associations of PCBs with coronary heart disease (CHD)-related outcomes in a cohort of Great Lakes sport fish consumers. METHODS: The Great Lakes Sport Fish Consumer cohort was established in the early 1990's. Eight hundred nineteen participants were followed from 1993 to 2017. Serum PCBs were measured in 1994/1995 (baseline), in 2001, and in 2004, while health history questionnaires were administered in 1996, 2003, 2010, and 2017. Cox models were used to prospectively investigate associations of total PCBs and PCB groupings, based on aryl hydrocarbon receptor activity, with incident self-reported physician diagnosis of coronary heart disease (CHD), myocardial infarction (MI), and angina pectoris. RESULTS: A 2-fold increase in phenobarbital-type PCBs was associated with a 72% increase in likelihood of self-reported incident diagnosis of CHD (HR=1.72, 95% CI: 1.06-2.81; p=0.0294). Similar results were observed for total PCBs (HR=1.68, 95% CI: 1.05-2.69; p=0.0306) and mixed methacholine/phenobarbital type (mixed-type) PCBs (HR=1.60, 95% CI: 1.02-2.52; p=0.0427), but not methacholine-type PCBs. PCBs were not strongly associated with risk of MI or angina. CONCLUSIONS: This study presents evidence that exposure to PCBs increases the risk of developing coronary heart disease. Given the large number of risk factors and causal pathways for CHD, future research is required to better understand biological mechanisms of action for PCBs on CHD.

Operative trends for pancreatic and hepatic malignancies during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic disrupted routine health care, including many elective and non-cancer operations in the United States. Most hepato-pancreato-biliary malignancy patients require outpatient imaging, tissue sampling, and staging, and many undergo neoadjuvant therapy before operative intervention. The aims of this study were to evaluate the effect of the COVID-19 pandemic on hepato-pancreato-biliary oncologic operations and to determine whether trends in neoadjuvant therapy were altered by the pandemic. METHODS: Adult patients in the United States undergoing oncologic operations for pancreatic, primary and secondary hepatic malignancies, with or without neoadjuvant therapy, were extracted from the Vizient Clinical Data Base. Control chart analysis was used to plot trends over time and to determine whether changes were statistically significant. Wilcoxon rank-sum tests also compared monthly operative volume from pre-pandemic (12 month) and pandemic (28 months) periods. RESULTS: A total of 36,553 patients were identified over 40 months. Mean monthly pancreatic oncologic operations were unaffected by the pandemic (P = .257). Operations for pancreatic oncologic operations with prior neoadjuvant therapy increased throughout the pandemic (P = .002). Oncologic operations for primary and secondary hepatic malignancies were significantly reduced for 4 and 2 months, respectively, at the beginning of the pandemic but returned to their pre-pandemic baseline within 4 months (P = .169 and P = .598). CONCLUSION: Pancreatic operation volumes for cancer did not change, but pancreatic operations after neoadjuvant therapy continued to increase during the pandemic. Operations for hepatic malignancy were transiently disrupted but quickly normalized. These observations suggest that surgery for hepato-pancreato-biliary malignancies was prioritized during the pandemic.

Adverse Cardiac Events of Hypercholesterolemia Are Enhanced by Sitagliptin Administration in Sprague Dawley Rats.

Background: Cardiovascular disease (CVD) affects millions worldwide and is the leading cause of death among non-communicable diseases. Western diets typically comprise of meat and dairy products, both of which are rich in cholesterol (Cho) and methionine (Met), two well-known compounds with atherogenic capabilities. Despite their individual effects, literature on a dietary combination of the two in the context of CVD are limited. An additional interest was to investigate the cardioprotective potential of sitagliptin, an anti-type 2 diabetic drug. Thus, we hypothesized that atherogenic feeding would result in adverse cardiac effects and would attenuate upon sitagliptin administration. Methods: Six-week-old adult male Sprague-Dawley rats were fed either a control (Con), high Met (1.5%), high Cho (2.0%), or high Met (1.5%) + high Cho (2.0%) diet for 35 days. They were orally gavaged with vehicle (water) or sitagliptin (100 mg/kg/d) from day 10 through 35. On day 36, rats were euthanized, and tissues were collected for analysis. Results: Histopathological evaluation revealed a reduction in myocardial striations and increased collagen deposition in hypercholesterolemia (HChol), responses that became exacerbated upon sitagliptin administration. Cardiac pro-inflammatory and pro-fibrotic responses were adversely impacted in similar fashion. The addition of Met to Cho (MC) attenuated all adverse structural and biochemical responses, with or without sitagliptin. Conclusion: Adverse cardiac outcomes in HChol were enhanced with sitagliptin administration and such effects were alleviated by Met. Our findings could be significant for understanding the risk-benefit of sitagliptin in type 2 diabetics who are known to consume atherogenic diets.

Autism-associated brain differences can be observed in utero using MRI.

Developmental changes that occur before birth are thought to be associated with the development of autism spectrum disorders. Identifying anatomical predictors of early brain development may contribute to our understanding of the neurobiology of autism spectrum disorders and allow for earlier and more effective identification and treatment of autism spectrum disorders. In this study, we used retrospective clinical brain magnetic resonance imaging data from fetuses who were diagnosed with autism spectrum disorders later in life (prospective autism spectrum disorders) in order to identify the earliest magnetic resonance imaging-based regional volumetric biomarkers. Our results showed that magnetic resonance imaging-based autism spectrum disorder biomarkers can be found as early as in the fetal period and suggested that the increased volume of the insular cortex may be the most promising magnetic resonance imaging-based fetal biomarker for the future emergence of autism spectrum disorders, along with some additional, potentially useful changes in regional volumes and hemispheric asymmetries.

Patients' subjective well-being: Determinants and its usage as a metric of healthcare service quality.

It is commonly suggested that patients' subjective well-being (SWB) can be affected by pre-treatment conditions and treatment experiences, and hence SWB can be used to measure and improve healthcare quality. With data collected in a hospital in the UK (N = 446), we investigated the determinants of patients' SWB and evaluated its use in healthcare research. Our findings showed strong relationships between pre-treatment conditions and patients' SWB: anxiety and depression negatively predicted SWB across all three domains, mobility positively predicted the life satisfaction and happiness domains, while the ability to self care and pain and discomfort also predicted SWB in some domains. In contrast, patients' satisfaction with the treatment only played minor roles in determining SWB, much less so the characteristics of their nurses. The general lack of associations between treatment experiences and patient's SWB highlighted the challenges of using SWB to measure healthcare quality and inform policy making.

Divergence of Grainy head affects chromatin accessibility, gene expression, and embryonic viability in Drosophila melanogaster.

Pioneer factors are critical for gene regulation and development because they bind chromatin and make DNA more accessible for binding by other transcription factors. The pioneer factor Grainy head (Grh) is present across metazoans and has been shown to retain a role in epithelium development in fruit flies, nematodes, and mice despite extensive divergence in both amino acid sequence and length. Here, we investigate the evolution of Grh function by comparing the effects of the fly (Drosophila melanogaster) and worm (Caenorhabditis elegans) Grh orthologs on chromatin accessibility, gene expression, embryonic development, and viability in transgenic D. melanogaster. We found that the Caenorhabditis elegans ortholog rescued cuticle development but not full embryonic viability in Drosophila melanogaster grh null mutants. At the molecular level, the C. elegans ortholog only partially rescued chromatin accessibility and gene expression. Divergence in the disordered N-terminus of the Grh protein contributes to these differences in embryonic viability and molecular phenotypes. These data show how pioneer factors can diverge in sequence and function at the molecular level while retaining conserved developmental functions at the organismal level.

Effects of neural oscillation power and phase on discrimination performance in a visual tilt illusion.

Neural oscillations reflect fluctuations in the relative excitation/inhibition of neural systems1,2,3,4,5 and are theorized to play a critical role in canonical neural computations6,7,8,9 and cognitive processes.10,11,12,13,14 These theories have been supported by findings that detection of visual stimuli fluctuates with the phase of oscillations prior to stimulus onset.15,16,17,18,19,20,21,22,23 However, null results have emerged in studies seeking to demonstrate these effects in visual discrimination tasks,24,25,26,27 raising questions about the generalizability of these phenomena to wider neural processes. Recently, we suggested that methodological limitations may mask effects of phase in higher-level sensory processing.28 To test the generality of phasic influences on perception requires a task that involves stimulus discrimination while also depending on early sensory processing. Here, we examined the influence of oscillation phase on the visual tilt illusion, in which a center grating has its perceived orientation biased away from the orientation of a surround grating29 due to lateral inhibitory interactions in early visual processing.30,31,32 We presented center gratings at participants' subjective vertical angle and had participants report whether the grating appeared tilted clockwise or counterclockwise from vertical on each trial while measuring their brain activity with electroencephalography (EEG). In addition to effects of alpha power and aperiodic slope, we observed robust associations between orientation perception and alpha and theta phase, consistent with fluctuating illusion magnitude across the oscillatory cycle. These results confirm that oscillation phase affects the complex processing involved in stimulus discrimination, consistent with its purported role in canonical computations that underpin cognition.

Preoperative Predictors of Patient-Reported Outcomes Following Arthroscopic Partial Meniscectomy.

The purpose of this study is to evaluate the effect of patient demographics and injury characteristics on post-arthroscopic partial meniscectomy (post-APM) patient-reported outcomes (PROs). We hypothesize that the presence of high-grade (Kellgren-Lawrence grades 3-4) arthritis at any location of the knee (medial and lateral compartments, patella, trochlea), comorbidities (psychiatric history, chronic pain, diabetes, smoking, body mass index [BMI] ≥ 30), and lower scores on preoperative patient-reported measures (36-Item Short Form Health Survey [SF-36]) would predict poor outcomes after APM. We conducted a single-center prospective study of 92 patients who underwent APM surgery for associated knee pain. General demographic information and PROs were prospectively collected using SF-12, SF-36, and International Knee Documentation Committee (IKDC) surveys presurgery and at 6-month follow-up. Postsurgery outcomes were patient-reported satisfaction (yes/no) and obtaining a patient-acceptable symptom state (PASS) on IKDC. Data were analyzed with odds ratios (ORs), binomial logistic regression, and Mann-Whitney U test using IBM SPSS software. Demographic and injury characteristics that were poor prognostic indicators (had a decreased likelihood of obtaining PASS on IKDC postsurgery) included having Medicaid insurance (OR: 0.056; 0.003-1.00), chronic pain (OR: 0.106; 0.013-0.873), acute injury (OR: 0.387; 0.164-0.914), and high-grade (KL grades 3-4) medial compartment arthritis (OR: 0.412; 0.174-0.980), and preoperative SF-36 physical health score (PHS; p = 0.023) and mental health score (MHS; p = 0.006) values less than 47 and 48, respectively. Additionally, former smoking history (OR: 0.271; 0.079-0.928) showed a lower likelihood of being satisfied postsurgery. Not having psychiatric history (OR: 14.925; p < 0.001; increased likelihood of obtaining PASS on IKDC score postsurgery) and not having patellar arthritis (OR: 4.082; p = 0.025; increased likelihood of PASS on IKDC) were positive prognostic indicators. This study identifies predictive factors of poor outcomes post-APM; particularly, it highlights the usefulness of SF-36 surveys prior to APM surgery. Patients with low SF-36 score preoperatively may not find APM acceptable. Additional attention should be put on patient demographics (such as psychiatric history, chronic pain, and insurance type) and injury characteristics (presence of arthritis and acute injury) prior to performing APM. LEVEL OF EVIDENCE: II.

Delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate exposures reported to America's Poison Centers.

INTRODUCTION: Since the passage of the Farm Bill in 2018, the availability of synthetic tetrahydrocannabinols has increased, including delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate. The objective of this study is to investigate the characteristics of delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate exposures reported to United States poison centers from 2021 to 2022. METHODS: National Poison Data System data were analyzed, including year, individual demographics, substance category and type, reason for exposure, highest level of health care received, and medical outcome. United States Census Bureau data were used to calculate population-based rates. RESULTS: There were 5,022 reported cases involving delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate as the primary substance reported to United States poison centers from 1 January 2021 to 31 December 2022. The rate of exposure per 100,000 United States population increased by 89.1 percent from 0.55 in 2021 to 1.04 in 2022. Children less than 6 years old accounted for 30.1 percent of cases, with a mode at age 2 years (representing 8.9 percent of cases). Most cases involved delta-8 tetrahydrocannabinol (98.1 percent), were single-substance exposures (94.3 percent), or occurred in a residence (95.9 percent). Ingestions accounted for 94.2 percent of cases, including 95.1 percent among children less than 6 years old. The leading reason for exposure was unintentional-general (40.2 percent), followed by abuse (33.1 percent). The most common related clinical effects were mild central nervous system depression (25.0 percent), tachycardia (23.0 percent), and agitation (15.6 percent). More than one-third (38.4 percent) of cases experienced a serious medical outcome, and 10.3 percent were admitted to a noncritical care unit and 5.3 percent to a critical care unit. DISCUSSION AND LIMITATIONS: The National Poison Data System is limited by its passive surveillance design. Delta-8 tetrahydrocannabinol, delta-10 tetrahydrocannabinol, and tetrahydrocannabinol-O acetate have toxic effects, and reports to United States poison centers increased from 2021 to 2022. Unintentional ingestions by young children are of particular concern. CONCLUSIONS: Opportunities exist to improve regulation, with accompanying enforcement, of these products and to educate the public about their potential toxicity.

Timing of radiotherapy (RT) after radical prostatectomy (RP): long-term outcomes in the RADICALS-RT trial (NCT00541047).

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for prostate-specific antigen (PSA) failure. PATIENTS AND METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, preoperative PSA≥10 ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ('Adjuvant-RT') or an observation policy with salvage RT for PSA failure ('Salvage-RT') defined as PSA≥0.1 ng/ml or three consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5 Gy/20 fractions or 66 Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant-metastasis (FFDM), designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10 years with Adjuvant-RT. Secondary outcome measures were biochemical progression-free survival, freedom from non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; hazard ratio (HR)<1 favours Adjuvant-RT. RESULTS: Between October 2007 and December 2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with a median age of 65 years. Ninety-three percent (649/697) Adjuvant-RT reported RT within 6 months after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10-year FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 [95% confidence interval (CI) 0.43-1.07, P=0.095]. Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95% CI 0.667-1.440, P=0.917). Adjuvant-RT reported worse urinary and faecal incontinence 1 year after randomisation (P=0.001); faecal incontinence remained significant after 10 years (P=0.017). CONCLUSION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy. TRIAL IDENTIFICATION: RADICALS, RADICALS-RT, ISRCTN40814031, NCT00541047.